Notre Dame flags Src and SHP2 switches

University of Notre Dame researchers said a new computational pipeline can identify pH-sensitive “switches” in proteins that help control signaling linked to cancer and other diseases. In a study published in *Science Signaling*, the team reported that the method flagged ionizable amino-acid networks in SHP2 and Src, two signaling proteins with established roles in growth control and cancer biology. The researchers said the workflow can scan hundreds of proteins in a few days, compressing a process that previously required years of one-by-one investigation. ### What exactly did the Notre Dame team build? The Notre Dame group described the method as a computational pipeline designed to find proteins whose activity changes with intracellular pH and then map the molecular features responsible for that sensitivity. The university said the system screens protein structures for pH-sensitive elements and helps identify candidate mechanisms before wet-lab work begins. (research.nd.edu) Katharine White, a biochemist at Notre Dame and the study’s corresponding author, said the goal is to narrow the search space before experiments. The university’s release said the pipeline is intended to help researchers prioritize which proteins and which sites are most promising for laboratory verification and drug-development follow-up. (research.nd.edu) ### Why were SHP2 and Src the proteins highlighted in the study? The *Science Signaling* paper applied the pipeline to SHP2 and Src because both are SH2 domain-containing signaling proteins involved in pathways that regulate cell behavior. The paper said SHP2 phosphatase activity was pH-sensitive in vitro and in cells, while Src kinase activity also changed with pH. (research.nd.edu) The study identified specific residues in SHP2 — His116 and Glu252 — whose mutation abolished pH-sensitive activity, according to the paper abstract and the university summary. For Src, the researchers reported that mutating a network of ionizable amino acids abolished pH-sensitive activity, supporting the idea that these residues act together as regulatory switches rather than as isolated sites. (science.org) ### What does “pH-sensitive switch” mean here? Intracellular pH shifts can alter the charge state of ionizable amino acids, and the Notre Dame team said those changes can reshape how proteins interact with their own regulatory domains. In both SHP2 and Src, the paper said constant-pH molecular dynamics simulations supported an allosteric mechanism in which pH-dependent binding of inhibitory SH2 domains affects the catalytic domain. (science.org) The paper’s framing is narrower than a claim that pH alone causes cancer. Instead, the authors reported that pH-dependent regulation operates alongside established control systems. In Src, for example, the study said pH-sensitive regulation remained evident even with epidermal growth factor stimulation or with a phosphomimetic substitution that promotes autoinhibition. (science.org) ### Why does the speed of the pipeline matter? Notre Dame said the throughput is the main operational advance. The university release said researchers can now scan hundreds of proteins in a few days, replacing a slower workflow that historically required extensive protein-by-protein characterization. (science.org) The paper also reported that the approach was extended across SH2 domain-containing signaling proteins, where the team identified evolutionarily conserved putative pH-sensing networks. That means the method is not limited to the two showcase proteins and can be used to rank additional candidates for experimental testing. ### What happens next? (research.nd.edu) The Notre Dame researchers said the computational results are meant to guide lab validation, not replace it. The university release said the next step is to use the flagged sites to focus experiments on proteins and residues most likely to show meaningful pH-sensitive behavior. (pubmed.ncbi.nlm.nih.gov) The study appeared in *Science Signaling* in November 2025, and the paper lists White and colleagues including P.K. Van Dyck, L. Piszkin, E.A. Gorski, Eduarda Tartarella Nascimento, Joshua A. Abebe, Logan M. Hoffmann and Jeffrey W. Peng. The article and the university release are the main public sources for the findings and the experimental follow-up path. (science.org) (research.nd.edu)